We disclosed a specific biological pathway for the observed cell damage when stimulated by the crystalline SiO2 nanoparticles (NPs), i.e., both mitochondrion multiplication and DNA fragmentation occur upon the initial reactive oxygen species (ROS) generation, with the former causing further increases of the ROS level in the cell, and eventually leads to catastrophic effect on cell physiology. Such damage becomes nontrivial only in the absence of p53 gene, which regulates cells' anti-oxidation and detoxification. This genotoxic effect is absent in cells treated with amorphous SiO2 NPs.